In immune and infection mediated vasculitides, intravascular activation of peripheral blood phagocytes can cause these cells to release highly reactive oxygen metabolites and powerful enzymes. Although phagocytes normally reserve these weapons for destroying invading microorganisms, the pathological activation of neutrophils or monocytes will result in tissue injury and destruction. Phagocytes triggered within the blood vessel lumen have the potential to attack the endothelial cell lining and the underlying basement membrane. Damage to either of these structures can lead to altered vascular permeability, thrombosis, renal or pulmonary dysfunction and possibly atherosclerosis. In this study we will examine the ability of human phagocytes (neutrophils and monocytes) triggered with stimuli likely to be encountered in pathological states (immune complexes, tissue directed antibodies, activated complement components, bacterial peptides) to damage monolayers of cultured, human endothelial cells. In vitro model systems will be constructed to mimic in vivo pathological states with specific emphasis placed on 1) assessing the potential of the triggered phagocytes to damage either the endothelial cell or its underlying basement membrane, 2) characterizing the relative role of oxygen metabolites and neutral proteinases in mediating these injuries and, 3) identifying the final mediators of endothelial cell damage and basement membrane degradation. An understanding of the phagocyte-endothelial cell-basement membrane interaction will not only provide specific information into the pathogenesis of immune-mediated vascular injury but will also provide new insights into the biochemistry of the inflammatory process. Utilizing this information, rational therapeutic interventions can be designed that could attenuate inflammatory damage in a wide range of pathological states.